The goal of this proposal is to study the mechanisms by which the LIM-domain only (LMO) proteins affect psychostimulant-induced behaviors in Drosophila and in mice. In a genetic screen for Drosophila mutants with altered responsiveness to acute nicotine and cocaine exposure, multiple alleles of the Lmo gene were isolated. LMOs are highly-conserved proteins that regulate the activity of LIM-homeodomain (LIM-HD) factors. These, in turn, regulate multiple aspects of the final differentiated state of neurons, such as their neurochemical identity and receptor expression profile. LMOs are thus ideally suited to modulate in a subtle manner the sensitivity of the nervous system to drugs of abuse. We propose to use genetic, molecular, genomic, and neuroanatomical approaches to determine when, where and how Lmo functions in the Drosophila brain to regulate psychostimulant responsiveness. In addition, we will begin to translate this information to a mammalian system by studying the role of LMOs in psychostimulant-induced behaviors in mice. The Specific Aims of the proposal are as follows. First, we will use inducible gene expression strategies to determine whether LMO acts in the developing and/or adult nervous system to regulate drug behaviors in Drosophila. Second, we will use a series of genetic experiments in Drosophila to define the identity of the functional LIM-HD partner(s) for LMO in the context of cocaine and nicotine sensitivity. Third, we will use transcriptional profiling to define the genes whose expression is altered by loss or gain of Lmo function in Drosophila. Fourth, we will test the role of mouse Lmo homologs in several behavioral paradigms that measure the acute stimulant and rewarding properties of cocaine. LMOS and LMO4 were chosen for this analysis as they are expressed in brain regions implicated in the reinforcing properties of abused drugs. [unreadable] [unreadable] Together, these experiments will provide novel insights into the mechanisms by which psychostimulant sensitivity is controlled in the nervous system. LMOs have been shown to function as highly dynamic transcriptional modulators and are thus well-suited to regulate adaptive and potentially long-lasting changes in nervous system physiology. Exposure to drugs of abuse leads to long-term changes in the brain that are believed to cause the addicted state. LMOs are attractive candidate molecules to mediate these changes. The relevance of this project is that it will help us understand how abused drugs, such as cocaine, cause long-lasting changes in the brain. By interfering with these changes, or reversing them, we should be able to develop therapies to help treat drug addicts. [unreadable] [unreadable] [unreadable]